Is CASK p.Ala683Val (c.2048C>T) pathogenic?

CASK p.Ala683Val (c.2048C>T) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-01). AlphaMissense: likely pathogenic (0.9803); Very rare (popmax 0.00436%, amr); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Ala683Val (c.2048C>T)?

CASK p.Ala683Val (c.2048C>T) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Ala683Val (c.2048C>T) in the general population?

CASK p.Ala683Val (c.2048C>T) is very rare (popmax 0.00436%, amr) (gnomAD).

What do computational predictors say about CASK p.Ala683Val (c.2048C>T)?

AlphaMissense predicts likely pathogenic (score 0.9803) — an in-silico prediction, not a clinical call.

CASK p.Ala683Val

c.2048C>T · rs767030499 · VCV537748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00436%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.9803	likely pathogenic
REVEL	0.846	moderately pathogenic-leaning
SaProt	LLR -12.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 11 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00436% Admixed American · 2/45,903 alleles

Filtering AF 0.000722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00027%

Overall 0.000291% 3/1,030,795 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00436%	22,952
European (non-Finnish)	0.00012%	834,328

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CASK
Protein: p.Ala683Val
Coding: c.2048C>T
MANE Select: NM_001367721
dbSNP: rs767030499
Type: single nucleotide variant
Location: chrX:41542798 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 683: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the 'required for interaction with nrxn1 (via c-terminal tail)' region

Full CASK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Intellectual disability, CASK-related, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Ala683Ser Uncertain significance ★ ⚠ same residue
CASK p.Ala683Thr Uncertain significance ★ ⚠ same residue
CASK p.Arg489Gln Pathogenic/Likely pathogenic ★★ same condition
CASK p.Ala359Val Uncertain significance ★★ ⚠ same condition
CASK p.Ala833Thr Uncertain significance ★★ ⚠ same condition
CASK p.Arg130Cys Uncertain significance ★★ ⚠ same condition
CASK p.Arg572His Uncertain significance ★★ ⚠ same condition
CASK p.Arg61Trp Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cask-p-ala683val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown